Dr. Ledbetter's laboratory is interested in both the mechanisms causing constitutional chromosomal abnormalities such as deletions, marker chromosomes, and uniparental disomy, and the consequences of these events in terms of gene dosage imbalance and genomic imprinting effects on human development. The laboratory uses a broad array of conventional cytogenetic, molecular cytogenetic, and molecular biology technologies to investigate several human dosage and/or imprinting disorders as model systems. Lissencephaly, a neuronal migration defect leading to profound mental retardation, is used as a model for a haploinsufficiency disorder in man. Deletions within chromosome band 17p13.3 are detected in 40% of patients with isolated lissencephaly and all patients with the Miller-Dieker syndrome. Deletion mapping led to the isolation of a gene, LIS1, responsible for lissencephaly when hemizygous deletions or point mutations are present. Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct mental retardation disorders caused by deficiency of a paternally expressed gene(s) or maternally expressed gene(s), respectively, on chromosome 15. We have cloned the critical region of 4 Mb in a yeast artificial chromosome (YAC) contig, and defined a large domain of multiple imprinted genes in this region. Four hot spots for chromosomal breakage have been identified and cloned in YACs, and their molecular characterization will significantly contribute to our knowledge of mechanisms of structural chromosomal rearrangement. Finally, our laboratory completed a major effort to clone a complete set of human telomeric probes suitable for FISH analysis of cryptic translocations and deletions. This resource will have a major impact on the ability to perform high-resolution deletion detection in clinical populations and cancer.